SignificanceDamage to neuronal networks in the central nervous system typically results in permanent functional deficits; however, the regenerative capacity of injured neurons can be dramatically augmented by local innate immune responses. Here we investigated the molecular and cellular events that participate in immune-mediated repair of severed optic nerve axons in the mouse. We show that intraocular administration of particulate β-glucan engages the immune receptor dectin-1 expressed on retina-resident microglia and infiltrating leukocytes, to trigger enhanced axonal regeneration. Delayed administration of β-glucan by two days is as effective as administration at the time of injury, suggesting a large therapeutic window. These data elucidate a new pathway of immune-mediated neural repair that may be targeted to reverse neurological disability.